Hemoglobin pathology is studied with emphasis on the role of subunit interaction in hemoglobin variants which display altered properties due to changes in intramolecular subunit interactions or intermolecular subunit interactions. Hemoglobins with altered intramolecular subunit interactions generally display modified oxygen binding equilibria which often impair delivery of oxygen to the tissues. The variations can arise from either subunit interactions that are too strong, as in the case of the high affinity hemoglobin Chesapeake, or subunit interactions which are excessively weak, as in the case of the low affinity hemoglobin Kansas. Many other hemoglobin variants lie in between these two extremes. The proposed correlations of subunit dissociation with details of the oxygen properties for various hemoglobins should aid considerably in understanding the basis of malfunction. Pathologies related to intermolecular subunit interactions are particularly striking in the case of sickling hemoglobins, such as hemoglobin S. In this case, individual molecules aggregate into extended molecular arrays which distort the red blood cell and disturb blood flow. The proposed studies on the molecular mechanism of sickling, with the analytical ultracentrifuge, should provide much needed information on the mode of aggregation of hemoglobin S, indicate strategies in the design of anti-sickling agents of therapeutic value, and provide a convenient assay of sickling agents. Development of new techniques for these experiments is planned, especially improvements of methods for monitoring macromolecular interactions in the analytical ultracentrifuge. In addition the application of these methods to supermolecular assembly in other systems of biological interest, such as ribosome assembly and protein membrane interactions, will be explored.